Hyperammonemia encephalopathy

A. Hyperammonemia, encephalopathy, or hepatotoxicity related to valproic acid therapy. 

Ferenci P, Pappas SC, Munson PJ, Jones AE Changes in glutamate receptors on synaptic membranes associated with hepatic encephalopathy or hyperammonemia in the rabbit. Hepatology 1984 4 25-29. 

Wu, X.Z., M. Yamada, T. Hobo, and S. Suzuki. 1989. Uranine sensitized chemiluminescence for alternative determinations of copper (II) and free cyanide by the flow injection method. Anal. Chem. 61 1505-1510. Yamamoto, H.A. 1989. Hyperammonemia, increased brain neutral and aromatic amino acid levels, and encephalopathy induced by cyanide in mice. Toxicol. Appl. Pharmacol. 99 415 120. 

Yamamoto H. 1989. Hyperammonemia, increased brain neutral and aromatic amino acid levels, and encephalopathy induced by cyanide in mice. Toxicol Appl Pharmacol 99 415-420. 

Hyperammonemia and encephalopathy associated with concomitant valproic acid use Administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In most cases, symptoms and signs abated with discontinuation of either drug. 

Carbonic anhydrase inhibitor-induced alkalinization of the urine decreases urinary excretion of NH4+ (by converting it to rapidly reabsorbed NH3) and may contribute to the development of hyperammonemia and hepatic encephalopathy in patients with cirrhosis. 

There have been attempts to unravel the mechanism of fluorouracil-induced hyperammonemia, lactic acidosis, and encephalopathy, a rare adverse effect associated with high-dose therapy. The cause is not known, although Krebs cycle metabolism is almost certainly involved (415,416). 

In two other cases the addition of topiramate was thought to have precipitated valproate-induced hyperammonemic encephalopathy (1172). Recovery occurred after withdrawal of valproate or topiramate. The authors suggested that topiramate may have contributed to the hyperammonemia by inhibiting carbonic anhydrase and cerebral glutamine synthetase. 

Valproate-induced hyperammonemic encephalopathy has been reviewed (1177). Proton magnetic resonance spectroscopy was performed in a patient with valproate-induced hyperammonemic encephalopathy there was a significant fall in the choline and myoinositol resonances and an increase in glutamine in the hyperintense basal ganglia lesions (1178). A similar pattern has been observed in other hyperammonemic encephalopathies, such as hepatic encephalopathy. In another study in seven patients with valproate-related hyperammonemia serum or cerebrospinal fluid glutamine concentrations were initially raised in most patients, sometimes in the absence of hyperammonemia (1179). 

The relationship of hyperammonemia to valproic acid-associated encephalopathies has been questioned after a study of ammonia concentrations in 55 asymptomatic patients taking valproic acid showed that 29 had ammonia concentrations above the reference range, the highest being 140 pmol/l (1180). 

It is difficult to establish a relation between valproate encephalopathy and increased serum ammonium concentrations. Valproate-induced hyperammonemic encephalopathy has been reported in several single case reports, but still it is difficult to ascertain whether hyperammonemia or valproic acid is the cause of the encephalopathy. In one case valproate was used in combination with lithium, which in itself could have caused encephalopathy by displacement of protein binding or other mechanisms, regardless of hyperammonemia (1181). In a second case it was also impossible to evaluate the effect of hyperammonemia on the level of consciousness, since it involved a woman who took valproic acid (30 g) in addition to... 

Rao K. V. and Norenberg M. D. (2001). Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia. Metab Brain Dis. 16 67-78. 

Citrulline is exchanged for ornithine across the inner mitochondrial membrane by ORNT-1. Ornithine is produced in the cytosol as the final step in the urea cycle and must be returned to the mitochondrial matrix for transcarbamoyla-tion by OTC. A second ornithine-citrulline antiporter (ORNT-2) is also expressed in the liver mitochondria and may attenuate the severity of disease in patients with HHH (Hyperammonemia, Hyperornithinemia, Homocitrullinuria) disease due to ORNT-1 deficiency. This disorder typically manifests later in life with intermittent hyperammonemic encephalopathy and protein aversion. Intramitochondrial ornithine deficiency causes both hyperammonemia and hyperornithinemia due to a lack of substrate for OTC. Homocitrullinuria occurs due to the use of lysine by OTC as an alternate substrate. The diagnosis is confirmed by mutation analysis. 

The final step of the urea cycle is the cleavage of arginine to release urea and regenerate ornithine. Ornithine then reenters the mitochondria via the ORNT-1 ornithine-citrulline antiporter. ARG-1 is a cytosolic homotrimeric enzyme of 35-kd monomers that is expressed in fiver and red blood cells. A second mitochondrial arginase (ARG-2) most likely plays a role in nitric oxide synthesis and is most abundant in brain, kidney, and prostate. ARG-1 deficiency is unique among the urea cycle deficiencies as patients do not present with hyperammonemia and encephalopathy but rather develop progressive spasticity of the lower limbs. Biochem-... 

Treatment for patients with a UCD can be divided into two parts acute management of hyperammonemic encephalopathy and long-term control to prevent further episodes of hyperammonemia while maintaining normal growth and development. 

Of as yet unknown consequence to the brain and nervous system, there are many studies indicating that valproic acid promotes a variety of potentially dangerous viruses (e.g., Fan et al., 2005). Both valproic acid and carbamazepine cause a small increase in the rate of major congenital malformations in infants (Wide et al., 2004). Acute and potentially fatal pancreatitis has been reported with valproic acid (e.g., Grauso-Eby et al., 2003). Liver failure is a known problem as well. Valproic acid is known to cause hyperammonemia with encephalopathy (e.g., McCall et al., 2004). Severe and even lethal skin disorders can occur with all of the antiseizure medications now used as mood stabilizers. The various adverse effects of valproic acid and other mood stabilizers are not nearly as benign as physicians believe in their eagerness to switch patients from lithium. 

Because the CNS is sensitive to ammonia, its metabolism in the brain and the neurotoxicity associated with hyperammonia and hepatic encephalopathy (the proximate source of damage in the latter is also ammonia) is reviewed here. Hepatic encephalopathy (HE) or congenital and acquired hyperammonemia result in excessive ammonia accumulation within the CNS. The condition is due... 

Vogels, B.A.PM., Karlsen, O.T., Maas, M.A.W., Bovee, WJVIJVI.J., Chamidean, RA.FJVI. L-Omithine vs. L-omithine-L-aspartate as a treatment for hyperammonemia-induced encephalopathy in rats. J. Hepatol. 1997 26 174-182... 

Encephalopathy secondary to hyperammonemia has been reported in those rare cases of hver failure that are associated with high doses of aspirin, and this also forms a major feature of Reye s syndrome (see the section on Liver in this monograph). 

Kimura A, Yoshida I, Ono E, Matsuishi T, Yoshino M, Yamashita F, Yamamoto M, Hashimoto T, Shinka T, Kuhara T, et al. Acute encephalopathy with hyperammonemia and dicarboxyhc aciduria during calcium hopantenate therapy a patient report. Brain Dev 1986 8(6) 601-5. 

Weight gain, gastrointestinal symptoms, hair loss, and tremor are relatively common adverse effects. Sedation, fatigue, dizziness, headache, ataxia, insomnia, and behavioral problems are less frequent than with other anticonvulsants. Hyperammonemia is relatively common, but it is often asymptomatic. Fatal liver failure has an incidence of up to 1 600 in young infants, but is extremely rare in adults. Uncommon effects include parkinsonism, encephalopathy, pseudoatrophy of the brain, pancreatitis, and disorders of hemostasis (especially thrombocytopenia). 

Sedation, fatigue, dizziness, headache, ataxia, and insomnia are less frequent with valproate than with other anticonvulsants. However, encephalopathy, sometimes associated with hyperammonemia and/or liver failure, has been described on several occasions, with symptoms ranging from acute confusion to stnpor and even deep coma (SEDA-18, 69) (9). The stnpor tends to be associated with bilaterally synchronons high-voltage, slow-wave EEG activity. Psychiatric symptoms and increased seizure frequency can also occur. Although in some cases valproate-induced stupor can be associated with increased epileptiform activity, it appeared to be triggered by a cortical non-epileptic mechanism in six... 

Hyperammonemias are caused by inborn errors of ureagenesis and organic acidemias, liver immaturity (transient hyperammonemia of the newborn), and liver failure (hepatic encephalopathy). Neonatal hyperammonemias are characterized by vomiting, lethargy, lack of appetite, seizures, and coma. The underlying defects can be identified by appropriate laboratory measurements (e.g., assessment of metabolic acidosis if present and characterization of organic acids, urea cycle intermediates, and glycine). 

Transient rises of transaminase levels have been observed, without evidence of liver toxicity. Hyperammonemia with encephalopathy has been observed with therapeutic levels and in overdose, and without other evidence of hepatic dysfunction. 

IV. Diagnosis is based on the history of exposure and typical findings of CNS depression and metabolic disturbances. The differential diagnosis is broad and in-oludes most CNS depressants. Encephalopathy and hyperammonemia may mimio Reye s syndrome. 

However, encephalopathies with a metabohc basis tend to be the most problanatic for infants or children, with functional outcomes dependent upon timely and pradent interventions. Three varieties of metabolic encephalopathy in children are discussed here. The first two are closely related. Inborn (genetic) errors of metabolism can present in the newborn as severe encephalopathy from hyperammonemia alone. When a metabolic error presents months to years later, a degree of hepatic insufficiency may complicate the metabolic derangement. In acute or fulminant hepatic failure of any etiology (i.e., infections, drug-induced, toxin-related), the rise in serum ammonia may be only moderate but other factors contribute to the ensuing encephalopathy, which may be devastating within days. 

Valproate may contribute to hyperammonemia by inhibiting carbamoylphosphate synthetase-I, the enzyme that begins the urea cycle. Phenobarbital may potentiate the toxic effect of valproate. The electroencephalogram in severe hyperammonemic encephalopathy exhibits continuous generalized slowing, a predominance of theta and delta waves, bursts of frontal intermittent rhythmic delta activity, and triphasic waves (Segura-Bruna et al., 2006). 

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